Various grinding media, such as stainless steel, zirconium silicate, zirconium oxide, glass, and the like, typically in the form of spherical beads, are commonly used in various mills, including media mills, for grinding materials. Heretofore, efforts have been made to control the size and size range of drug particles in pharmaceutical compositions by a variety of methods, including various milling techniques, such as airjet milling and wet milling. However, there tends to be a bias in the pharmaceutical arts against milling techniques, particularly wet milling, due to concerns associated with contamination. For example, in the preparation of pharmaceuticals for oral and parenteral applications, it is desirable to have total contamination, e.g., of heavy metals, below about 10 parts per million. The need to control and minimize contamination is particularly critical in the milling of parenteral products due to potential safety issues associated with injection of contaminants.
Liversidge et al, U.S. Pat. No. 5,145,684, and European Patent Application 498,492, describe dispersible particles consisting of a drug substance or an x-ray contrast agent having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm. The particles are prepared by dispersing a drug substance or imaging agent in a liquid dispersion medium and wet grinding in the presence of rigid grinding media.
Bruno et al, commonly-owned U.S. patent application Ser. No. 07/981,639 filed Nov. 25, 1992 entitled Method for Grinding Pharmaceutical Substances discloses polymeric grinding media for fine grinding pharmaceutical compositions. Bruno et al disclose that the media can be in the size range of 0.1-3 mm (100-3000 microns). The media specifically exemplified in the working examples have a mean particle size in the range of 0.3-0.6 mm (300-600 microns).
In practicing the methods described by Liversidge et al and Bruno et al, dispersions comprising therapeutic and diagnostic agents having particle sizes as small as about 100 nm have been obtained on some occasions. However, for many applications, e.g., when further increased bioavailability and/or targeting to a specific tissue site is desired, it would be highly advantageous to produce dispersions free of unacceptable contamination having a particle size of less than 100 nm.